Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Am J Hum Genet ; 105(3): 549-561, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447097

RESUMO

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

2.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021819

RESUMO

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

3.
Pediatr Diabetes ; 19(1): 171-179, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28370959

RESUMO

BACKGROUND: Insulin autoimmune syndrome (IAS), characterized by glycemic dysregulation and life-threatening hypoglycemia, can occur in patients with type 1 diabetes (T1D). Diagnostic confirmation is complex but important in order to ensure timely initiation of definitive therapy. AIMS: We aimed to quantitate the degree of immunoglobulin-insulin complex (IIC) formation and its effects on glycemic control in a patient with T1D and IAS compared with T1D and non-T1D controls and before and after therapeutic plasma exchange (TPE). MATERIALS & METHODS: The prospective descriptive study was conducted between June 2015 and December 2015 in a quaternary children's hospital in Brisbane, Australia. Percent Free "Immunoreactive" Insulin (%FII) as assessed by polyethylene glycol precipitation studies and its relationship to plasma glucose and serum insulin concentration. RESULTS: Samples from the patient with T1D and IAS demonstrated lower mean %FII compared to T1D (23.8 ± 2.0 vs 52.0 ± 6.7; P < .0001) and non-T1D (23.8 ± 2.0 vs 102.9 ± 2.7; P < .0001) controls. This was associated with loss of glycemic predictability and frequent severe hypoglycemia. TPE increased %FII (23.8 ± 2.0 before TPE vs 83.6 ± 2.5 after TPE, P < .0001) and reestablished plasma glucose responsiveness to exogenous insulin. DISCUSSION: IAS should be considered in T1D patients with unexplained glycemic instability and hypoglycemia. The laboratory plays an integral diagnostic role. CONCLUSION: TPE is an effective method for removing IICs and normalizing insulin-mediated glucose responses.


Assuntos
Doenças Autoimunes/terapia , Diabetes Mellitus Tipo 1/complicações , Hipoglicemia/imunologia , Insulina/imunologia , Troca Plasmática , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Criança , Diabetes Mellitus Tipo 1/imunologia , Humanos , Masculino , Estudos Prospectivos
4.
J Immunol ; 2017 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-28794229

RESUMO

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.

5.
J Allergy Clin Immunol ; 139(3): 933-949, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27554822

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4+ T cells to disease pathogenesis in these patients has not been thoroughly investigated. OBJECTIVE: We sought to investigate the phenotype and function of DOCK8-deficient CD4+ T cells to determine (1) intrinsic and extrinsic CD4+ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. METHODS: We performed in-depth analysis of the CD4+ T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4+ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. RESULTS: DOCK8-deficient memory CD4+ T cells were biased toward a TH2 type, and this was at the expense of TH1 and TH17 cells. In vitro polarization of DOCK8-deficient naive CD4+ T cells revealed the TH2 bias and TH17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. CONCLUSION: Investigations into the DOCK8-deficient CD4+ T cells provided an explanation for some of the clinical features of this disorder: the TH2 bias is likely to contribute to atopic disease, whereas defects in TH1 and TH17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndromes de Imunodeficiência/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Alérgenos/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Leucócitos Mononucleares/imunologia , Masculino , Adulto Jovem
6.
Front Immunol ; 7: 357, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27703454

RESUMO

One out of three pediatric sepsis deaths in high income countries occur in previously healthy children. Primary immunodeficiencies (PIDs) have been postulated to underlie fulminant sepsis, but this concept remains to be confirmed in clinical practice. Pseudomonas aeruginosa (P. aeruginosa) is a common bacterium mostly associated with health care-related infections in immunocompromised individuals. However, in rare cases, it can cause sepsis in previously healthy children. We used exome sequencing and bioinformatic analysis to systematically search for genetic factors underpinning severe P. aeruginosa infection in the pediatric population. We collected blood samples from 11 previously healthy children, with no family history of immunodeficiency, who presented with severe sepsis due to community-acquired P. aeruginosa bacteremia. Genomic DNA was extracted from blood or tissue samples obtained intravitam or postmortem. We obtained high-coverage exome sequencing data and searched for rare loss-of-function variants. After rigorous filtrations, 12 potentially causal variants were identified. Two out of eight (25%) fatal cases were found to carry novel pathogenic variants in PID genes, including BTK and DNMT3B. This study demonstrates that exome sequencing allows to identify rare, deleterious human genetic variants responsible for fulminant sepsis in apparently healthy children. Diagnosing PIDs in such patients is of high relevance to survivors and affected families. We propose that unusually severe and fatal sepsis cases in previously healthy children should be considered for exome/genome sequencing to search for underlying PIDs.

8.
Nat Commun ; 6: 8718, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26522830

RESUMO

Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.


Assuntos
Cardiomiopatias/genética , Síndromes de Imunodeficiência/genética , Íntrons , Retardo Mental Ligado ao Cromossomo X/genética , Osteocondrodisplasias/genética , Mutação Puntual , Processamento de RNA , RNA Nuclear Pequeno/genética , Doenças Retinianas/genética , Alelos , Sequência de Bases , Pré-Escolar , Nanismo/genética , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Masculino , Microcefalia/genética , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Linhagem , RNA Nuclear Pequeno/química , Regiões não Traduzidas
9.
J Exp Med ; 212(6): 855-64, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25941256

RESUMO

Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.


Assuntos
Fator de Transcrição STAT3/metabolismo , Linfócitos T/citologia , Separação Celular , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Interleucinas/metabolismo , Células Matadoras Naturais/citologia , Leucócitos Mononucleares/citologia , Linfócitos/citologia , Mutação , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina-12/metabolismo , Receptores de Interleucina-21/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
10.
J Exp Med ; 210(12): 2739-53, 2013 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-24218138

RESUMO

Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Memória Imunológica , Plasmócitos/imunologia , Plasmócitos/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos B/citologia , Diferenciação Celular , Linhagem da Célula , Humanos , Interleucina-10/metabolismo , Subunidade alfa de Receptor de Interleucina-21/deficiência , Subunidade alfa de Receptor de Interleucina-21/genética , Subunidade alfa de Receptor de Interleucina-21/metabolismo , Interleucinas/metabolismo , Mutação , Plasmócitos/citologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
11.
J Allergy Clin Immunol ; 132(2): 400-11.e9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23830147

RESUMO

BACKGROUND: The capacity of CD8(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown. OBJECTIVE: We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. METHODS: Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro. RESULTS: Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8(+) T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells. However, this defect was overcome by T-cell receptor engagement. CONCLUSION: The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R-deficient subjects.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Memória Imunológica , Síndrome de Job/genética , Mutação , Fator de Transcrição STAT3/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Humanos , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Síndrome de Job/imunologia , Síndrome de Job/patologia , Receptores de Interleucina-21/genética , Receptores de Interleucina-21/imunologia , Receptores de Interleucina-21/metabolismo , Fator de Transcrição STAT3/genética
12.
Blood ; 119(17): 3997-4008, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22403255

RESUMO

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rß1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.


Assuntos
Diferenciação Celular , Interleucina-12/farmacologia , Mutação/genética , Receptores de Interleucina-12/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Linfócitos T Auxiliares-Indutores/citologia , TYK2 Quinase/genética , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Humanos , Hospedeiro Imunocomprometido , Ativação Linfocitária , Camundongos , Receptores de Interleucina-12/deficiência , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/deficiência , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , TYK2 Quinase/metabolismo , Fatores de Transcrição/metabolismo
13.
Blood ; 118(26): 6824-35, 2011 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-22039266

RESUMO

SCID resulting from mutations in IL2RG or JAK3 is characterized by lack of T and natural killer cells; B cells are present in normal number, but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses after HCT in IL2RG/JAK3 deficiency results from poor donor B-cell engraftment and defective γc-dependent cytokine signaling in host B cells. To test this, and to identify which γc cytokine(s) is critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3 deficiency. Lack of donor B-cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B-cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10, or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B-cell proliferation, plasmablast differentiation, and antibody secretion in patients with donor B cells, but not in patients with autologous B cells. These data imply that IL-21-mediated signaling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients after HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B-cell immunity in IL2RG/JAK3 SCID after transplantation.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Subunidade gama Comum de Receptores de Interleucina/imunologia , Interleucinas/imunologia , Linfócitos B/metabolismo , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Células Cultivadas , Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Memória Imunológica/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Interleucinas/metabolismo , Janus Quinase 3/genética , Janus Quinase 3/imunologia , Janus Quinase 3/metabolismo , Mutação , Ligação Proteica , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/metabolismo , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/metabolismo
14.
J Exp Med ; 207(1): 155-71, 2010 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-20048285

RESUMO

Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.


Assuntos
Diferenciação Celular/fisiologia , Memória Imunológica/fisiologia , Interleucinas/imunologia , Plasmócitos/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/fisiologia , Formação de Anticorpos/fisiologia , Antígenos/genética , Antígenos/imunologia , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Interleucinas/genética , Plasmócitos/citologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/genética , Fatores de Tempo
15.
J Paediatr Child Health ; 45(9): 481-6, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19702611

RESUMO

Cow's milk protein allergy is a condition commonly managed by general practitioners and paediatricians. The diagnosis is usually made in the first 12 months of life. Management of immediate allergic reactions and anaphylaxis includes the prevention of accidental food ingestion and provision of an adrenaline autoinjector, if appropriate. By contrast, the clinical course of delayed food-allergic manifestations is characterised by chronicity, and is often associated with nutritional or behavioural sequelae. Correct diagnosis of these non-IgE-mediated conditions may be delayed due to a lack of reliable diagnostic markers. This review aims to guide clinicians in the: (i) diagnostic evaluation (skin prick testing or measurement of food-specific serum IgE levels; indications for diagnostic challenges for suspected IgE- and non-IgE-mediated food allergy), (ii) dietary treatment, (iii) assessment of response to treatment, (iv) differential diagnosis and further diagnostic work-up in non-responders, (v) follow-up assessment of tolerance development and (vi) recommendations for further referral.


Assuntos
Hipersensibilidade a Leite/tratamento farmacológico , Proteínas do Leite/efeitos adversos , Anafilaxia , Animais , Austrália , Bovinos , Pré-Escolar , Protocolos Clínicos , Humanos , Hipersensibilidade Imediata/induzido quimicamente , Lactente , Recém-Nascido , Hipersensibilidade a Leite/diagnóstico , Hipersensibilidade a Leite/fisiopatologia
16.
Med J Aust ; 188(2): 109-12, 2008 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-18205586

RESUMO

Three types of infant formula (soy, extensively hydrolysed and amino acid) may be appropriate for treating cows milk protein allergy. Selection of a formula depends on the allergy syndrome to be treated. Extensively hydrolysed formula is recommended as first choice for infants under 6 months of age for treating immediate cows milk allergy (non-anaphylactic), food protein-induced enterocolitis syndrome, atopic eczema, gastrointestinal symptoms and food protein-induced proctocolitis. Soy formula is recommended as first choice for infants over 6 months of age with immediate food reactions, and for those with gastrointestinal symptoms or atopic dermatitis in the absence of failure to thrive. Amino acid formula is recommended as first choice in anaphylaxis and eosinophilic oesophagitis. If treatment with the initial formula is not successful, use of an alternative formula is recommended.


Assuntos
Fórmulas Infantis , Hipersensibilidade a Leite/prevenção & controle , Animais , Austrália , Bovinos , Dermatite Atópica/etiologia , Dermatite Atópica/prevenção & controle , Gastroenterite/etiologia , Gastroenterite/prevenção & controle , Humanos , Lactente , Hipersensibilidade a Leite/complicações , Proteínas do Leite/efeitos adversos , Proteínas de Soja/administração & dosagem
17.
Med J Aust ; 185(9): 517-22, 2006 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-17137459

RESUMO

Eczema is common, occurring in 15%-20% of infants and young children. For some infants it can be a severe chronic illness with a major impact on the child's general health and on the family. A minority of children will continue to have eczema as adults. The exact cause of eczema is not clear, but precipitating or aggravating factors may include food allergens (most commonly, egg) or environmental allergens/irritants, climatic conditions, stress and genetic predisposition. Management of eczema consists of education; avoidance of triggers and allergens; liberal use of emollients or topical steroids to control inflammation; use of antihistamines to reduce itch; and treatment of infection if present. Treatment with systemic agents may be required in severe cases, but must be supervised by an immunologist. Urticaria ("hives") may affect up to a quarter of people at some time in their lives. Acute urticaria is more common in children, while chronic urticaria is more common in adults. Chronic urticaria is not life-threatening, but the associated pruritus and unsightly weals can cause patients much distress and significantly affect their daily lives. Angioedema coexists with urticaria in about 50% of patients. It typically affects the lips, eyelids, palms, soles and genitalia. Management of urticaria is through education; avoidance of triggers and allergens (where relevant); use of antihistamines to reduce itch; and short-term use of corticosteroids when antihistamine therapy is ineffective. Referral is indicated for patients with resistant disease.


Assuntos
Eczema/diagnóstico , Eczema/terapia , Urticária/diagnóstico , Urticária/terapia , Adulto , Criança , Doença Crônica , Eczema/etiologia , Humanos , Lactente , Masculino , Urticária/etiologia
18.
Australas J Dermatol ; 47(1): 49-52, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16405484

RESUMO

SUMMARY A 9-year-old girl presented with a 6-month history of inflamed tender nodules in the pretibial area. These eventually healed leaving depressed areas of atrophy and loss of subcutaneous tissue. Histology showed a predominantly lymphocytic lobular panniculitis, consistent with connective tissue panniculitis. Investigations revealed an elevated thyroid stimulating hormone, elevated thyroid antiperoxidase antibody and a weakly positive antinuclear antibody (titre 1 in 40). She was commenced on hydroxychloroquine 300 mg daily, which resulted in resolution of the panniculitis. She developed focal vitiligo on the thighs. This gradually improved with 0.1% mometasone furoate ointment. The hydroxychloroquine dose was tapered to 200 mg daily after 12 months, then to 100 mg daily after 18 months therapy. Her thyroid autoantibody levels continued to rise and the hydroxychloroquine was increased again to 300 mg daily. She became borderline hypothyroid. Hashimoto's thyroiditis was diagnosed. Thyroxine was instituted with a resultant improvement in her thyroid blood tests. The lipoatrophy has not developed further during 2-year follow up.


Assuntos
Tecido Conjuntivo/patologia , Paniculite/diagnóstico , Tireoidite Autoimune/diagnóstico , Vitiligo/diagnóstico , Biópsia por Agulha , Criança , Tecido Conjuntivo/fisiopatologia , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hidroxicloroquina/uso terapêutico , Imuno-Histoquímica , Paniculite/complicações , Paniculite/tratamento farmacológico , Medição de Risco , Índice de Gravidade de Doença , Tireoidite Autoimune/complicações , Tireoidite Autoimune/tratamento farmacológico , Tiroxina/uso terapêutico , Vitiligo/complicações , Vitiligo/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA